Glucose and glycogen affects Ca transient during fatigue to a greater extent in the least than in the most fatigue resistant mouse FDB fibers.

The overall objective was to determine how no extracellular glucose and/or low glycogen content affect fatigue kinetics in mouse flexor digitorum brevis (FDB) single muscle fibers. High glycogen content (Hi GLY), near normal in situ level, was obtained by incubating fibers in culture medium containing glucose and insulin while low glycogen content (Lo GLY), at about 19% of normal in situ level, was achieved by incubating fibers without glucose. Neither Lo GLY nor the absence of extracellular glucose (0GLU) affected tetanic [Ca] prior to fatigue.

Pannexin 1 dysregulation in Duchenne muscular dystrophy and its exacerbation of dystrophic features in mdx mice.

Background: Duchenne muscular dystrophy (DMD) is associated with impaired muscle regeneration, progressive muscle weakness, damage, and wasting. While the cause of DMD is an X-linked loss of function mutation in the gene encoding dystrophin, the exact mechanisms that perpetuate the disease progression are unknown. Our laboratory has demonstrated that pannexin 1 (Panx1 in rodents; PANX1 in humans) is critical for the development, strength, and regeneration of male skeletal muscle.

A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na,K-ATPase, Na and K ions, and on plasma K concentration-historical developments.

This historical review traces key discoveries regarding K and Na ions in skeletal muscle at rest and with exercise, including contents and concentrations, Na,K-ATPase (NKA) and exercise effects on plasma [K] in humans. Following initial measures in 1896 of muscle contents in various species, including humans, electrical stimulation of animal muscle showed K loss and gains in Na, Cl and H0, then subsequently bidirectional muscle K and Na fluxes. After NKA discovery in 1957, methods were developed to quantify muscle NKA activity via rates of ATP hydrolysis, Na/K radioisotope fluxes, [H]-ouabain binding and phosphatase activity.

The potassium-glycogen interaction on force and excitability in mouse skeletal muscle: implications for fatigue.

A reduced muscle glycogen content and potassium (K ) disturbances across muscle membranes occur concomitantly during repeated intense exercise and together may contribute to skeletal muscle fatigue. Therefore, we examined whether raised extracellular K concentration ([K ] ) (4 to 11 mM) interacts with lowered glycogen to reduce force production. Isometric contractions were evoked in isolated mouse soleus muscles (37°C) using direct supramaximal field stimulation.

Angiotensin 1-7 increases fiber cross-sectional area and force in juvenile mouse skeletal muscle.

Recent studies reported that in skeletal muscle angiotensin 1-7 (Ang 1-7), via its receptor Mas (MasR), prevents the atrophy induced by angiotensin II and by cast immobilization; it also improves muscle integrity and function in the mdx mouse, a muscular dystrophy model. The objectives of this study were to document ) the extent of the Ang 1-7's hypertrophic effect in terms of muscle mass and muscle fiber cross-sectional area (CSA), ) how Ang 1-7 affects muscle contractile function in terms of twitch and tetanic force, force-frequency relationship, and ) whether the effect involves MasR. Wild-type and MasR-deficient [Mas receptor knockout mouse model ()] mice were treated with Ang 1-7 (100 ng/kg body wt·min using an osmotic pump) for 4 or 16 wk.

The peak force-resting membrane potential relationships of mouse fast- and slow-twitch muscle.

We endeavored to understand the factors determining the peak force-resting membrane potential () relationships of isolated slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice (25°C), especially in relation to fatigue. Interrelationships between intracellular K activity ([Formula: see text]), extracellular K concentration ([K]), resting , action potentials, and force were studied. The large resting variation was mainly due to the variability of [Formula: see text].

Angiotensin 1-7 prevents the excessive force loss resulting from 14- and 28-day denervation in mouse EDL and soleus muscle.

Denervation leads to muscle atrophy, which is described as muscle mass and force loss, the latter exceeding expectation from mass loss. The objective of this study was to determine the efficiency of angiotensin (Ang) 1-7 at reducing muscle atrophy in mouse extensor digitorum longus (EDL) and soleus following 14- and 28-d denervation periods. Some denervated mice were treated with Ang 1-7 or diminazene aceturate (DIZE), an ACE2 activator, to increase Ang 1-7 levels.

Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy.

Background: Mouse models of mild spinal muscular atrophy (SMA) have been extremely challenging to generate. This paucity of model systems has limited our understanding of pathophysiological events in milder forms of the disease and of the effect of SMN depletion during aging.

Methods: A mild mouse model of SMA, termed Smn;SMN2, was generated by crossing Smn;SMN2 and Smn mice.

Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles.

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A.

Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles.

Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized.

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions.

Muscle-specific expression of the RNA-binding protein Staufen1 induces progressive skeletal muscle atrophy via regulation of phosphatase tensin homolog.

Converging lines of evidence have now highlighted the key role for post-transcriptional regulation in the neuromuscular system. In particular, several RNA-binding proteins are known to be misregulated in neuromuscular disorders including myotonic dystrophy type 1, spinal muscular atrophy and amyotrophic lateral sclerosis. In this study, we focused on the RNA-binding protein Staufen1, which assumes multiple functions in both skeletal muscle and neurons.

KATP channel deficiency in mouse FDB causes an impairment of energy metabolism during fatigue.

The skeletal muscle ATP-sensitive K (K) channel is crucial in preventing fiber damage and contractile dysfunction, possibly by preventing damaging ATP depletion. The objective of this study was to investigate changes in energy metabolism during fatigue in wild-type and inwardly rectifying K channel (Kir6.2)-deficient (Kir6.

Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis.

The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (HyperKPP) are not fully understood. Using a knock-in HyperKPP mouse model harboring the M1592V NaV1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin-sensitive Na(+) influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K(+)]e, myofiber-type composition, and myofiber damage.

Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse.

The diaphragm muscle of hyperkalemic periodic paralysis (HyperKPP) patients and of the M1592V HyperKPP mouse model rarely suffers from the myotonic and paralytic symptoms that occur in limb muscles. Enigmatically, HyperKPP diaphragm expresses the mutant NaV1.4 channel and, more importantly, has an abnormally high Na(+) influx similar to that in extensor digitorum longus (EDL) and soleus, two hindlimb muscles suffering from the robust HyperKPP abnormalities.

Combinatorial therapeutic activation with heparin and AICAR stimulates additive effects on utrophin A expression in dystrophic muscles.

Upregulation of utrophin A is an attractive therapeutic strategy for treating Duchenne muscular dystrophy (DMD). Over the years, several studies revealed that utrophin A is regulated by multiple transcriptional and post-transcriptional mechanisms, and that pharmacological modulation of these pathways stimulates utrophin A expression in dystrophic muscle. In particular, we recently showed that activation of p38 signaling causes an increase in the levels of utrophin A mRNAs and protein by decreasing the functional availability of the destabilizing RNA-binding protein called K-homology splicing regulatory protein, thereby resulting in increases in the stability of existing mRNAs.

Changes in myoplasmic Ca2+ during fatigue differ between FDB fibers, between glibenclamide-exposed and Kir6.2-/- fibers and are further modulated by verapamil.

One objective of this study was to document how individual FDB muscle fibers depend on the myoprotection of KATP channels during fatigue. Verapamil, a CaV1.1 channel blocker, prevents large increases in unstimulated force during fatigue in KATP-channel-deficient muscles.

Properties of single FDB fibers following a collagenase digestion for studying contractility, fatigue, and pCa-sarcomere shortening relationship.

The objective of this study was to optimize the approach to obtain viable single flexor digitorum brevis (FDB) fibers following a collagenase digestion. A first aim was to determine the culture medium conditions for the collagenase digestion. The MEM yielded better fibers in terms of morphology and contractility than the DMEM.

Utrophin A is essential in mediating the functional adaptations of mdx mouse muscle following chronic AMPK activation.

Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin along muscle fibers. An attractive therapeutic avenue for DMD consists in the upregulation of utrophin A, a protein with high sequence identity and functional redundancy with dystrophin. Recent work has shown that pharmacological interventions that induce a muscle fiber shift toward a slower, more oxidative phenotype with increased expression of utrophin A confer morphological and functional improvements in mdx mice.